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Cockayne's Syndrome: case report of a successful pregnancy
BJOG: an International Journal of Obstetrics and Gynaecology September 2003, Vol. 110, pp. 871 –872
CASE REPORT
Cockayne’s Syndrome: case report of a successful pregnancy Soma Lahiria,*, Norman Daviesb Case report The patient had Cockayne’s Syndrome diagnosed at 12 years of age. Her early development had been normal. At the age of seven years, she had experienced the onset of photosensitivity, telangiectasia and poor growth had been noted. At the age of 12 years, she was investigated on account of extreme short stature (height and weight less than the first centile). She also had mild cerebellar signs, constricted visual fields, telangiectasia and photosensitivity. There was no evidence of intellectual deficiency and no family history of a similar disorder. A rectal biopsy showed a clearly defective response to ultraviolet-C and typical changes consistent with Cockayne’s Syndrome. Her first period occurred when she was 13 and she became pregnant four years later. Her height was 132 cm and she weighed 31 kg at her booking appointment. Her partner had no family history of Cockayne’s Syndrome and they were unrelated. Her pregnancy progressed normally to 23 weeks of gestation when she was admitted in preterm labour with the cervix fully dilated. Extreme contraction of the pelvic outlet prevented the passage of even a small fetus and a transverse lie was also present. A lower segment caesarean section was performed and the male fetus died within 4 hours due to extreme prematurity. She was advised against a future pregnancy and surrogacy was suggested. Fourteen weeks later she became pregnant again. She experienced abdominal pain and uterine contractions, from early in the second trimester, and was admitted to hospital at 18 weeks of gestation. Progressive growth of her uterus in the limited space of the abdominal cavity owing to her extremely small frame caused her discomfort and there were episodes of uterine contractions. She experienced shortness of breath as her pregnancy progressed. We administered betamethasone at 24 weeks, and sulindac 100 mg twice daily and nifedipine 10 mg twice daily from 25 weeks of gestation in an attempt to reduce amniotic fluid volume and decrease uterine contractions.
a
Barnsley General Hospital, Barnsley, UK The Jessop Wing, Tree Root Walk, Sheffield, UK
b
* Correspondence: Dr S. Lahiri, 55 Longley Farm View, Sheffield, S5 7JX, UK. D RCOG 2003 BJOG: an International Journal of Obstetrics and Gynaecology PII: S 1 4 7 0 - 0 3 2 8 ( 0 3 ) 0 1 6 9 0 - 2
At 34 weeks, caesarean section was performed due to the increasing restriction of the gravid uterus in the limited space of her abdominal cavity. A baby boy weighing 2.12 kg was delivered. She had an uneventful puerperium and the infant was healthy.
Discussion Cockayne’s Syndrome is a rare autosomal recessive disorder, first described in 19361. It is characterised by growth retardation, skeletal and retinal abnormalities, neurological defects and mental retardation. A prenatal diagnostic test is available2. It has been classified into three clinical subtypes3: classical (Type I), severe (Type II) and mild. Classical Cockayne’s Syndrome involves growth failure and neurodevelopmental and neurological dysfunction. Type II is early onset severe disease with death usually occurring by the age of six or seven years. In mild Cockayne’s Syndrome, early death does not occur and intelligence is normal. The other features of the disease are mild and later in onset. Affected individuals show postnatal growth failure and few adults exceed 20 kg in weight and 115 cm in height. The term ‘Cachectic dwarfism’ has been used to convey the greater decrease in weight compared with height. The neurological features include microcephaly, mental retardation, unsteady gait and tremor. Other clinical features include photosensitivity, cataract, optic atrophy, pigmented retinopathy, nystagmus and deafness. Cryptorchidism occurs in 30% of males and oligomenorrhoea, underdeveloped breasts, a small square pelvis and hypoplastic alae of the iliac bones in women4. The diagnosis is made on the clinical features and by fibroblasts showing decreased recovery of RNA synthesis following exposure to ultraviolet light5. In normal individuals, ultraviolet light depresses both DNA and RNA synthesis, which returns to normal soon after the exposure stops. In contrast, fibroblast and lymphoblastoid cells from patients with Cockayne’s Syndrome show greatly increased sensitivity to the killing affects of ultraviolet radiation, deficient recovery of RNA synthesis and defective repair of transcriptionally active genes6. This forms the basis of the laboratory diagnosis and has been attributed www.bjog-elsevier.com
872
CASE REPORT
to a specific deficiency in the ability to carry out preferential repair of damage in actively transcribed regions of DNA6. The primary defect involves components of the excision repair pathway: mutation detection, repair or repair coordination7. To our knowledge, this is the first reported case of successful pregnancy in a patient with Cockayne’s Syndrome. The limited capacity of the pelvis and abdomen is the major obstacle to the growth of the fetus. The prostaglandin synthetase inhibitor sulindac was used in an attempt to reduce the amniotic fluid volume, thus allowing more space for the growing fetus. Sulindac has been successfully used in the past to reduce amniotic fluid volume with no evidence of premature closure of the ductus arteriosus during prolonged therapy from the second and early third trimester8. It has a lesser effect on fetal urine output and on the ductus arteriosus when compared with indomethacin and may be a safer alternative9. Nifedipine was administered empirically to prevent premature labour. There was no evidence of any adverse effect on either the baby or the mother from these treatments.
References 1. Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1946;21:52. 2. Lehman AR, Francis AJ, Giannelli F. Prenatal diagnosis of Cockayne’s syndrome. Lancet 1985;2:486 (March). 3. Nance MA, Berry SA. Cockayne’s syndrome: review of 140 cases. Am J Med Genet 1992;42:68. 4. Jones KL. Cockayne syndrome. Smith’s Recognisable Patterns of Human Malformation, 4th edition. Philadelphia: Saunders, 1988:122 – 123. 5. Rainbow AJ, Howes M. A deficiency in the repair of UV and g-ray damaged DNA in fibroblasts from Cockayne’s syndrome. Mutat Res 1982;93:235. 6. Lehman AR, Kirk-Bell S, Mayne L. Abnormal kinetics of DNA synthesis in ultraviolet light-irradiated cells from patients with Cockayne’s syndrome. Cancer Res 1979;39:4238 – 4241. 7. Woods CG. DNA repair disorders. Arch Dis Child 1998;78: 178 – 184. 8. Peek MJ, McCarthy A, Kyle P, et al. Medical amnioreduction with sulindac to reduce cord complications in monochorionic twins. Am J Obstet Gynecol 1997;176:334 – 336. 9. Carlan SJ, O’Brien WF, O’Leary TD, et al. Randomised comparative trial of indomethacin and sulindac for the treatment of refractory preterm labour. Obstet Gynaecol 1992;79:223 – 228. Accepted 22 April 2003
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 871 – 872
CASE REPORT
Cockayne’s Syndrome: case report of a successful pregnancy Soma Lahiria,*, Norman Daviesb Case report The patient had Cockayne’s Syndrome diagnosed at 12 years of age. Her early development had been normal. At the age of seven years, she had experienced the onset of photosensitivity, telangiectasia and poor growth had been noted. At the age of 12 years, she was investigated on account of extreme short stature (height and weight less than the first centile). She also had mild cerebellar signs, constricted visual fields, telangiectasia and photosensitivity. There was no evidence of intellectual deficiency and no family history of a similar disorder. A rectal biopsy showed a clearly defective response to ultraviolet-C and typical changes consistent with Cockayne’s Syndrome. Her first period occurred when she was 13 and she became pregnant four years later. Her height was 132 cm and she weighed 31 kg at her booking appointment. Her partner had no family history of Cockayne’s Syndrome and they were unrelated. Her pregnancy progressed normally to 23 weeks of gestation when she was admitted in preterm labour with the cervix fully dilated. Extreme contraction of the pelvic outlet prevented the passage of even a small fetus and a transverse lie was also present. A lower segment caesarean section was performed and the male fetus died within 4 hours due to extreme prematurity. She was advised against a future pregnancy and surrogacy was suggested. Fourteen weeks later she became pregnant again. She experienced abdominal pain and uterine contractions, from early in the second trimester, and was admitted to hospital at 18 weeks of gestation. Progressive growth of her uterus in the limited space of the abdominal cavity owing to her extremely small frame caused her discomfort and there were episodes of uterine contractions. She experienced shortness of breath as her pregnancy progressed. We administered betamethasone at 24 weeks, and sulindac 100 mg twice daily and nifedipine 10 mg twice daily from 25 weeks of gestation in an attempt to reduce amniotic fluid volume and decrease uterine contractions.
a
Barnsley General Hospital, Barnsley, UK The Jessop Wing, Tree Root Walk, Sheffield, UK
b
* Correspondence: Dr S. Lahiri, 55 Longley Farm View, Sheffield, S5 7JX, UK. D RCOG 2003 BJOG: an International Journal of Obstetrics and Gynaecology PII: S 1 4 7 0 - 0 3 2 8 ( 0 3 ) 0 1 6 9 0 - 2
At 34 weeks, caesarean section was performed due to the increasing restriction of the gravid uterus in the limited space of her abdominal cavity. A baby boy weighing 2.12 kg was delivered. She had an uneventful puerperium and the infant was healthy.
Discussion Cockayne’s Syndrome is a rare autosomal recessive disorder, first described in 19361. It is characterised by growth retardation, skeletal and retinal abnormalities, neurological defects and mental retardation. A prenatal diagnostic test is available2. It has been classified into three clinical subtypes3: classical (Type I), severe (Type II) and mild. Classical Cockayne’s Syndrome involves growth failure and neurodevelopmental and neurological dysfunction. Type II is early onset severe disease with death usually occurring by the age of six or seven years. In mild Cockayne’s Syndrome, early death does not occur and intelligence is normal. The other features of the disease are mild and later in onset. Affected individuals show postnatal growth failure and few adults exceed 20 kg in weight and 115 cm in height. The term ‘Cachectic dwarfism’ has been used to convey the greater decrease in weight compared with height. The neurological features include microcephaly, mental retardation, unsteady gait and tremor. Other clinical features include photosensitivity, cataract, optic atrophy, pigmented retinopathy, nystagmus and deafness. Cryptorchidism occurs in 30% of males and oligomenorrhoea, underdeveloped breasts, a small square pelvis and hypoplastic alae of the iliac bones in women4. The diagnosis is made on the clinical features and by fibroblasts showing decreased recovery of RNA synthesis following exposure to ultraviolet light5. In normal individuals, ultraviolet light depresses both DNA and RNA synthesis, which returns to normal soon after the exposure stops. In contrast, fibroblast and lymphoblastoid cells from patients with Cockayne’s Syndrome show greatly increased sensitivity to the killing affects of ultraviolet radiation, deficient recovery of RNA synthesis and defective repair of transcriptionally active genes6. This forms the basis of the laboratory diagnosis and has been attributed www.bjog-elsevier.com
872
CASE REPORT
to a specific deficiency in the ability to carry out preferential repair of damage in actively transcribed regions of DNA6. The primary defect involves components of the excision repair pathway: mutation detection, repair or repair coordination7. To our knowledge, this is the first reported case of successful pregnancy in a patient with Cockayne’s Syndrome. The limited capacity of the pelvis and abdomen is the major obstacle to the growth of the fetus. The prostaglandin synthetase inhibitor sulindac was used in an attempt to reduce the amniotic fluid volume, thus allowing more space for the growing fetus. Sulindac has been successfully used in the past to reduce amniotic fluid volume with no evidence of premature closure of the ductus arteriosus during prolonged therapy from the second and early third trimester8. It has a lesser effect on fetal urine output and on the ductus arteriosus when compared with indomethacin and may be a safer alternative9. Nifedipine was administered empirically to prevent premature labour. There was no evidence of any adverse effect on either the baby or the mother from these treatments.
References 1. Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1946;21:52. 2. Lehman AR, Francis AJ, Giannelli F. Prenatal diagnosis of Cockayne’s syndrome. Lancet 1985;2:486 (March). 3. Nance MA, Berry SA. Cockayne’s syndrome: review of 140 cases. Am J Med Genet 1992;42:68. 4. Jones KL. Cockayne syndrome. Smith’s Recognisable Patterns of Human Malformation, 4th edition. Philadelphia: Saunders, 1988:122 – 123. 5. Rainbow AJ, Howes M. A deficiency in the repair of UV and g-ray damaged DNA in fibroblasts from Cockayne’s syndrome. Mutat Res 1982;93:235. 6. Lehman AR, Kirk-Bell S, Mayne L. Abnormal kinetics of DNA synthesis in ultraviolet light-irradiated cells from patients with Cockayne’s syndrome. Cancer Res 1979;39:4238 – 4241. 7. Woods CG. DNA repair disorders. Arch Dis Child 1998;78: 178 – 184. 8. Peek MJ, McCarthy A, Kyle P, et al. Medical amnioreduction with sulindac to reduce cord complications in monochorionic twins. Am J Obstet Gynecol 1997;176:334 – 336. 9. Carlan SJ, O’Brien WF, O’Leary TD, et al. Randomised comparative trial of indomethacin and sulindac for the treatment of refractory preterm labour. Obstet Gynaecol 1992;79:223 – 228. Accepted 22 April 2003
D RCOG 2003 Br J Obstet Gynaecol 110, pp. 871 – 872